Antifungal compositions with improved bioavailability

ABSTRACT

The present invention is concerned with novel pharmaceutical compositions of itraconazole which can be administered to a mammal suffering from a fungal infection, whereby a single such dosage form can be administered once daily, and in addition at any time of the day independently of the food taken in by said mammal. These novel compositions comprise particles obtainable by melt-extruding a mixture comprising itraconazole and an appropriate water-soluble polymer and subsequently milling said melt-extruded mixture.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 09/194,480,now U.S. Pat. No. 6,509,038, filed Nov. 19, 1998, which is a NationalStage application under 35 U.S.C. § 371 of PCT/EP97/02507 filed May 12,1997, which claims priority under 35 U.S.C. § 119 from EP 96.201.430.4,filed May 20, 1996 and EP 97.200.698.5, filed Mar. 7, 1997.

The present invention is concerned with novel pharmaceuticalcompositions of itraconazole which can be administered to a mammalsuffering from a fungal infection, whereby a single such dosage form canbe administered once daily, and in addition at any time of the dayindependently of the food taken in by said mammal. These novelcompositions comprise innovative particles obtainable by melt-extrudinga mixture comprising itraconazole and an appropriate water-solublepolymer and subsequently milling said melt-extruded mixture.

The development of pharmaceutical compositions having goodbioavailability of itraconazole, a compound that is practicallyinsoluble in aqueous media, remains one of the main challenges ofpharmaceutical development of this compound.

The term “practically insoluble” or “insoluble” is to be understood asdefined in the United States Pharmacopeia, i.e. a “very slightlysoluble” compound requiring from 1000 to 10,000 parts of solvent for 1part of solute; a “practically insoluble” or “insoluble” compoundrequiring more than 10,000 parts of solvent for 1 part of solute. Thesolvent referred to herein is water.

Itraconazole or(±)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one,is a broadspectrum antifungal compound developed for oral, parenteraland topical use and is disclosed in U.S. Pat. No. 4,267,179. Itsdifluoro analog, saperconazole or(±)-cis-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methoxypropyl)-3H-1,2,4-triazol-3-one,has improved activity against Aspergillus spp. and is disclosed in U.S.Pat. No. 4,916,134. Both itraconazole and saperconazole consist of amixture of four diastereoisomers, the preparation and utility of whichis disclosed in WO 93/19061: the diastereoisomers of itraconazole andsaperconazole are designated [2R-[2α,4α,4(R*)]], [2R-[2α,4α,4(S*)]],[2S-[2α,4α,4(S*)]] and [2S-[2α,4α,4(R*)]]. The term “itraconazole” asused hereinafter is to be interpreted broadly and comprises the freebase form and the pharmaceutically acceptable addition salts ofitraconazole, or of one of its stereoisomers, or of a mixture of two orthree or four of its stercoisomers. The preferred itraconazole compoundis the (±)-(2R*, 4S*) or (cis) forms of the free base form, having theChemical Abstracts Registry Number [84625-61-6]. The acid addition formsmay be obtained by reaction of the base form with an appropriate acid.Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric acid;nitric acid; phosphoric acid and the like; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic,2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-butenedioic,(E)-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.

In WO 94/05263, published on Mar. 17, 1994, there are disclosed beads orpellets having a 25–30 mesh sugar core (600–710 μm) coated with anantifungal, more particularly itraconazole (or saperconazole) and ahydrophilic polymer, more particularly, hydroxypropyl methylcellulose.Finished with a sealing film coat, such cores are referred to as beadsor pellets. The beads are filled into capsules suitable for oraladministration. The itraconazole is present in the drug-coating and isreleased readily from the surface of said coated beads, which leads toimproved bioavailability of itraconazole (or saperconazole) over thethen known oral dosage forms of itraconazole.

The preparation of coated beads as described in WO 94/05263 requiresspecial techniques and special equipment in a purpose-built plant.Indeed, the beads described in the prior art are prepared in a quitecomplex manner requiring a lot of manipulation steps. First, a drugcoating solution is prepared by dissolving into a suitable solventsystem appropriate amounts of the antifungal agent and a hydrophilicpolymer, preferably hydroxypropyl methylcellulose (HPMC). A suitablesolvent system comprises a mixture of methylene chloride and an alcohol.Said mixture should comprise at least 50% by weight of methylenechloride acting as a solvent for the drug substance. As hydroxypropylmethylcellulose does not dissolve completely in methylene chloride, atleast 10% alcohol has to be added. Subsequently, the 25–30 mesh sugarcores are drug-coated in a fluidized bed granulator equipped with abottom spray insert. Not only should the spraying rate be regulatedcarefully, but also temperature control in the fluidized bed granulatoris crucial. Hence, this process requires a lot of control in order toobtain a good quality product reproducibly. Moreover, this techniqueadequately, but still only partially solves the issue of residualorganic solvents, such as methylene chloride and methanol or ethanol,being present in the coating. In order to remove any solvents whichmight remain in the drug-coated intermediate product, an extra dryingstep is required. Subsequently, a seal coating is applied and this addsyet another two steps to the production process as it involves anotherdrying step, too.

About 460 mg beads, equivalent to about 100 mg itraconazole, are filledinto a hard-gelatin capsule (size 0) and two of these capsules areadministered once daily to a patient suffering from a fungal infection.The capsules are commercially available in many countries under theTrademark Sporanox™. In order to achieve the desired antifungal effect,it is essential that the two capsules are ingested at the end of a meal.This may seriously limit how easily the patients can comply with theirprescribed therapy; for example, some patients are not able to eatnormally or swallow medica-ments easily because of illness, nausea orbecause of fungal infection of the esophagus. It would therefore behighly desirable to have pharmaceutical dosage forms which can beadministered to a patient—or for that matter, to any mammal—at any timeof the day independently of food taken in, i.e. dosage forms which canbe administered to patients (mammals) in a fasted state. Dosage formswith a high drug content, one unit of which contains the required dailydose of the active ingredient instead of two such units, are anotherdesirable goal in the pharmaceutical development of itraconazole.

At this stage, it may be remarked that therapeutically effective plasmalevels of itraconazole can be maintained easily for at least 24 hours asits half-life is sufficiently long. The condition is that theitraconazole must reach the plasma. The absorption of dissolveditraconazole from the stomach is in itself not a problem. Thus, there isno need for a sustained release dosage form of itraconazole, animmediate release form will do just as well. In other words, the mainproblem with the administration of itraconazole in therapeuticallyeffective amounts is in the first place concerned with ensuring that asufficient amount of itraconazole remains in solution sufficiently longenough to allow it to get into the circulation, and that it does notconvert into a form that is not readily bioavailable, in particular intocrystalline itraconazole (which forms, for example, when itraconazoleprecipitates in an aqueous medium).

The present invention provides pharmaceutical compositions ofitraconazole and a water-soluble polymer which can be administered to amammal, in particular a human, suffering from a fungal infection,whereby a single such dosage form can be administered once daily, and inaddition at any time of the day independently of the food taken in bysaid mammal. The bioavailability of the drug from these dosage forms infasted and in fed mammals is comparable. The dosage forms can beprepared easily, for example by conventional tabletting techniques. Thedosage forms comprise a therapeutically effective amount of novelparticles as described in detail hereunder.

Said novel particles consist of a solid dispersion comprising

-   (a) itraconazole, or one of its stereoisomers, or a mixture of two    or three or four of its stereoisomers, and-   (b) one or more pharmaceutically acceptable water-soluble polymers.

The term “a solid dispersion” defines a system in a solid state (asopposed to a liquid or gaseous state) comprising at least twocomponents, wherein one component is dispersed more or less evenlythroughout the other component or components. When said dispersion ofthe components is such that the system is chemically and physicallyuniform or homogenous throughout or consists of one phase as defined inthermo-dynamics, such a solid dispersion will be called “a solidsolution” hereinafter. Solid solutions are preferred physical systemsbecause the components therein are usually readily bioavailable to theorganisms to which they are administered. This advantage can probably beexplained by the ease with which said solid solutions can form liquidsolutions when contacted with a liquid medium such as gastric juice. Theease of dissolution may be attributed at least in part to the fact thatthe energy required for dissolution of the components from a solidsolution is less than that required for the dissolution of componentsfrom a crystalline or microcrystalline solid phase.

The term “a solid dispersion” also comprises dispersions which are lesshomogenous throughout than solid solutions. Such dispersions are notchemically and physically uniform throughout or comprise more than onephase. For example, the term “a solid dispersion” also relates toparticles having domains or small regions wherein amorphous,microcrystalline or crystalline (a), or amorphous, microcrystalline orcrystalline (b), or both, are dispersed more or less evenly in anotherphase comprising (b), or (a), or a solid solution comprising (a) and(b). Said domains are regions within the particles distinctively markedby some physical feature, small in size compared to the size of theparticle as a whole, and evenly and randomly distributed throughout theparticle. Domains of (a) typically have a size of up to about 25 μm,preferably up to 20 μm.

The particles according to the present invention can be prepared byfirst preparing a solid dispersion of the components, and thenoptionally grinding or milling that dispersion. Various techniques existfor preparing solid dispersions including melt-extrusion, spray-dryingand solution-evaporation, melt-extrusion being preferred.

The melt-extrusion process comprises the following steps:

-   a) mixing the components (a) and (b),-   b) optionally blending additives with the thus obtained mixture,-   c) heating the thus obtained blend until one obtains a homogenous    melt,-   d) forcing the thus obtained melt through one or more nozzles; and-   e) cooling the melt till it solidifies.

The terms “melt” and “melting” should be interpreted broadly. For ourpurposes, these terms not only mean the alteration from a solid state toa liquid state, but can also refer to a transition to a glassy state ora rubbery state, and in which it is possible for one component of themixture to get embedded more or less homogeneously into the other. Inparticular cases, one component will melt and the other component(s)will dissolve in the melt thus forming a solution, which upon coolingmay form a solid solution having advantageous dissolution properties.

One of the most important parameters of melt extrusion is thetemperature at which the melt-extruder is operating. It was found thatthe operating temperature can easily range between about 120° C. andabout 300° C. At temperatures lower than 120° C., itraconazole will notdissolve completely in most water-soluble polymers and the extrudatewill not have the required bioavailability. In addition, the process isdifficult because of the high viscosity of the mixture. At temperaturesof more than 300° C. the water-soluble polymer may decompose to anunacceptable level. It may be noted that there is no need to feardecomposition of itraconazole at temperatures up to 300° C., since thisactive ingredient is thermally very stable.

The throughput rate is also of importance because even at relatively lowtemperatures the water-soluble polymer may start to decompose when itremains too long in contact with the heating element.

It will be appreciated that the person skilled in the art will be ableto optimize the parameters of the melt extrusion process within theabove given ranges. The working temperatures will also be determined bythe kind of extruder or the kind of configuration within the extruderthat is used. Most of the energy needed to melt, mix and dissolve thecomponents in the extruder can be provided by the heating elements.However, the friction of the material within the extruder may alsoprovide a substantial amount of energy to the mixture and aid in theformation of a homogenous melt of the components.

Spray-drying of a solution of the components also yields a soliddispersion of said components and may be a useful alternative to themelt-extrusion process, particularly in those cases where thewater-soluble polymer is not sufficiently stable to withstand theextrusion conditions and where residual solvent can effectively beremoved from the solid dispersion. Yet another possible preparationconsists of preparing a solution of the components, pouring saidsolution onto a large surface so as to form a thin film, and evaporatingthe solvent therefrom.

The solid dispersion product is milled or ground to particles having aparticle size of less than 600 μm, preferably less than 400 μm and mostpreferably less than 125 μm. The particle size proves to be an importantfactor determining the speed with which tablets having sufficienthardness can be manufactured on a large scale; the smaller theparticles, the faster the tabletting speed can be without detrimentaleffects on their quality. The particle size distribution is such thatmore than 70% of the particles (measured by weight) have a diameterranging from about 50 μm to about 500 μm, in particular from about 50 μmto about 200 μm and most in particular from about 50 μm to about 125 μm.Particles of the dimensions mentioned herein can be obtained by sievingthem through nominal standard test sieves as described in the CRCHandbook, 64^(th) ed., page F-114. Nominal standard sieves arecharacterized by the mesh/hole width (μm), DIN 4188 (mm), ASTM E11-70(No), Tyler® (mesh) or BS 410 (mesh) values. Throughout thisdescription, and in the claims hereinafter, particle sizes aredesignated by reference to the mesh/hole width in mm and to thecorresponding Sieve No. in the ASTM E11-70 standard.

Preferred are particles wherein the itraconazole is in a non-crystallinephase as these have an intrinsically faster dissolution rate than thosewherein part or all of the itraconazole is in a microcrystalline orcrystalline form.

Preferably, the solid dispersion is in the form of a solid solutioncomprising (a) and (b). Alternatively, it may be in the form of adispersion wherein amorphous or microcrystalline (a) or amorphous ormicrocrystalline (b) is dispersed more or less evenly in a solidsolution comprising (a) and (b).

The water-soluble polymer in the particles according to the presentinvention is a polymer that has an apparent viscosity of 1 to 100 mPs·swhen dissolved in a 2% aqueous solution at 20° C. solution. For example,the water-soluble polymer can be selected from the group comprising

-   alkylcelluloses such as methylcellulose,-   hydroxyalkylcelluloses such as hydroxymethylcellulose,    hydroxyethylcellulose, hydroxypropylcellulose and    hydroxybutylcellulose,-   hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose    and hydroxypropyl methylcellulose,-   carboxyalkylcelluloses such as carboxymethylcellulose,-   alkali metal salts of carboxyalkylcelluloses such as sodium    carboxymethylcellulose,-   carboxyalkylalkylcelluloses such as carboxymethylethylcellulose,-   carboxyalkylcellulose esters,-   starches,-   pectines such as sodium carboxymethylamylopectine,-   chitin derivates such as chitosan,-   polysaccharides such as alginic acid, alkali metal and ammonium    salts thereof, carrageenans, galactomannans, tragacanth, agar-agar,    gummi arabicum, guar gummi and xanthan gummi,-   polyacrylic acids and the salts thereof,-   polymethacrylic acids and the salts thereof, methacrylate    copolymers,-   polyvinylalcohol,-   polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl    acetate,-   polyalkylene oxides such as polyethylene oxide and polypropylene    oxide and copolymers of ethylene oxide and propylene oxide.

Non-enumerated polymers which are pharmaceutically acceptable and haveappropriate physico-chemical properties as defined hereinbefore areequally suited for preparing particles according to the presentinvention.

Preferred water-soluble polymers are hydroxypropyl methylcelluloses orHPMC. Said HPMC contains sufficient hydroxypropyl and methoxy groups torender it water-soluble. HPMC having a methoxy degree of substitutionfrom about 0.8 to about 2.5 and a hydroxypropyl molar substitution fromabout 0.05 to about 3.0 are generally water-soluble. Methoxy degree ofsubstitution refers to the average number of methyl ether groups presentper anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molarsubstitution refers to the average number of moles of propylene oxidewhich have reacted with each anhydroglucose unit of the cellulosemolecule. Hydroxypropyl methylcellulose is the United States AdoptedName for hypromellose (see Martindale, The Extra Pharmacopoeia, 29thedition, page 1435). In the four digit number “2910”, the first twodigits represent the approximate percentage of methoxyl groups and thethird and fourth digits the approximate percentage composition ofhydroxypropoxyl groups ; 5 mPs·s is a value indicative of the apparentviscosity of a 2% aqueous solution at 20° C.

The molecular weight of the HPMC normally affects both the releaseprofile of the milled extrudate as well as its physical properties. Adesired release profile can thus be designed by choosing an HPMC of anappropriate molecular weight; for immediate release of the activeingredient from the particles, a low molecular weight polymer ispreferred. High molecular weight HPMC is more likely to yield asustained release pharmaceutical dosage form. The molecular weight of awater-soluble cellulose ether is generally expressed in terms of theapparent viscosity at 20° C. of an aqueous solution containing twopercent by weight of said polymer. Suitable HPMC include those having aviscosity from about 1 to about 100 mPs·s, in particular form about 3 toabout 15 mPs·s, preferably about 5 mPs·s The most preferred type of HPMChaving a viscosity of 5 mPs·s., is the commercially available HPMC 29105 mPs·s, because this yields particles from which superior oral dosageforms of itraconazole can be prepared as will be discussed hereunder andin the experimental part.

The weight-by-weight ratio of (a):(b) is in the range of 1:1 to 1:17,preferably 1:1 to 1:5. In the case of (itraconazole):(HPMC 2910 5mPs·s), said ratio may range from about 1:1 to about 1:2, and optimallyis about 1:1.5 (or 2:3). The weight by weight ratio of itraconazole toother water-soluble polymers may be determined by a person skilled inthe art by straightforward experimentation. The lower limit isdetermined by practical considerations. Indeed, given thetherapeutically effective amount of itraconazole (from about 50 mg toabout 300 mg, preferably about 200 mg per day), the lower limit of theratio is determined by the maximum amount of mixture that can beprocessed into one dosage form of practical size. When the relativeamount of water-soluble polymer is too high, the absolute amount ofmixture needed to reach the therapeutic level will be too high to beprocessed into one capsule or tablet. Tablets, for example, have amaximum weight of about 1 g, and the extrudate can account for maximallyabout 90% (w/w) thereof. Consequently, the lower limit of the amount ofitraconazole over hydroxypropyl methyl cellulose will be about 1:17 (50mg itraconazole+850 mg water-soluble polymer).

On the other hand, if the ratio is too high, this means the amount ofitraconazole is relatively high compared to the amount of water-solublepolymer, then there is the risk that the itraconazole will not dissolvesufficiently in the water-soluble polymer, and thus the requiredbioavailability will not be obtained. The degree to which a compound hasdissolved into a water-soluble polymer can often be checked visually: ifthe extrudate is clear then it is very likely that the compound willhave dissolved completely in the water-soluble polymer. The 1:1 upperlimit is determined by the fact that above said ratio it was observedthat the extrudate resulting from extruding itraconazole with HPMC 29105 mPs·s is not “clear”, presumably due to the fact that not all of theitraconazole has dissolved in the HPMC. It will be appreciated that theupper limit of 1:1 may be underestimated for particular water-solublepolymers. Since this can be established easily but for theexperimentation time involved, solid dispersions wherein the ratio(a):(b) is larger than 1:1 are also meant to be comprised within thescope of the present invention.

Preferred particles are those obtainable by melt-extrusion of thecomponents and grinding, and optionally sieving. More in particular, thepresent invention concerns particles consisting of a solid solutioncomprising two parts by weight of itraconazole and three parts by weightof hydroxypropyl methylcellulose HPMC 2910 5 mPs·s, obtainable byblending said components, melt-extruding the blend at a temperature inthe range of 120° C.–300° C., grinding the extrudate, and optionallysieving the thus obtained particles. The preparation is easy to performand yields itraconazole particles that are free of organic solvent.

The particle as described hereinabove may further comprise one or morepharmaceutically acceptable excipients such as, for example,plasticizers, flavors, colorants, preservatives and the like. Saidexcipients should not be heat-sensitive, in other words, they should notshow any appreciable degradation or decomposition at the workingtemperature of the melt-extruder.

In the current itraconazole: HPMC 2910 5 mPs·s formulations, the amountof plasticizer is preferably small, in the order of 0% to 15% (w/w),preferably less than 5% (w/w). With other water-soluble polymers though,plasticizers may be employed in much different, often higher amountsbecause plasticizers as mentioned hereinbelow lower the temperature atwhich a melt of (a), (b) and plasticizer is formed, and this lowering ofthe melting point is advantagous where the polymeer has limited thermalstability. Suitable plasticizers are pharmaceutically acceptable andinclude low molecular weight polyalcohols such as ethylene glycol,propylene glycol, 1,2 butylene glycol, 2,3-butylene glycol, styreneglycol; polyethylene glycols such as diethylene glycol, triethyleneglycol, tetraethylene glycol; other polyethylene glycols having amolecular weight lower than 1,000 g/mol; polypropylene glycols having amolecular weight lower than 200 g/mol; glycol ethers such asmonopropylene glycol monoisopropyl ether; propylene glycol monoethylether; diethylene glycol monoethyl ether; ester type plasticizers suchas sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate,allyl glycollate; and amines such as monoethanolamine, diethanolamine,triethanolamine, monoisopropanolamine; triethylenetetramine,2-amino-2-methyl-1,3-propanediol and the like. Of these, the lowmolecular weight polyethylene glycols, ethylene glycol, low molecularweight polypropylene glycols and especially propylene glycol arepreferred.

Once the extrudate is obtained, it is milled and sieved and used as a“normal” ingredient to make pharmaceutical dosage forms.

The particles of the present invention can be formulated intopharmaceutical dosage forms comprising a therapeutically effectiveamount of particles. Although, at first instance, pharmaceutical dosageforms for oral administration such as tablets and capsules areenvisaged, the particles of the present invention can also be used toprepare pharmaceutical dosage forms e.g. for rectal administration.Preferred dosage forms are those adapted for oral administration shapedas a tablet. They can be produced by conventional tabletting techniqueswith conventional ingredients or excipients and with conventionaltabletting machines. In addition, they can be produced at substantiallylower cost than the coated cores. As mentioned above, an effectiveantifungal daily dose of itraconazole ranges from about 50 mg to about300 mg o.d., and preferably is about 200 mg o.d. When one considers thatthe weight-by-weight ratio of (a):(b) is maximally about 1:1, then itfollows that one dosage form will weigh at least 400 mg. In order tofacilitate the swallowing of such a dosage form by a mammal, it isadvantageous to give the dosage form, in particular tablets, anappropriate shape. Tablets that can be swallowed comfortably aretherefore preferably elongated rather than round in shape. Especiallypreferred are biconvex oblate tablets. As discussed hereunder in moredetail, a film coat on the tablet further contributes to the ease withwhich it can be swallowed.

Tablets that give an immediate release of itraconazole upon oralingestion and that have good bioavailability are designed in such amanner that the tablets disintegrate rapidly in the stomach (immediaterelease) and that the particles which are liberated thereby are keptaway from one another so that they do not coalesce, give local highconcentrations of itraconazole and the chance that the drug precipitates(bioavailability). The desired effect can be obtained by distributingsaid particles homogeneously throughout a mixture of a disintegrant anda diluent.

Suitable disintegrants are those that have a large coefficient ofexpansion. Examples thereof are hydrophilic, insoluble or poorlywater-soluble crosslinked polymers such as crospovidone (crosslinkedpolyvinylpyrrolidone) and croscarmellose (crosslinked sodiumcarboxymethylcellulose). The amount of disintegrant in immediate releasetablets according to the present invention may conveniently range fromabout 3 to about 15% (w/w) and preferably is about 7 to 9%, inparticular about 8.5% (w/w). This amount tends to be larger than usualin tablets in order to ensure that the particles are spread over a largevolume of the stomach contents upon ingestion. Because disintegrants bytheir nature yield sustained release formulations when employed in bulk,it is advantageous to dilute them with an inert substance called adiluent or filler.

A variety of materials may be used as diluents or fillers. Examples arespray-dried or anhydrous lactose, sucrose, dextrose, mannitol, sorbitol,starch, cellulose (e.g. micro-crystalline cellulose Avicel™), dihydratedor anhydrous dibasic calcium phosphate, and others known in the art, andmixtures thereof. Preferred is a commercial spray-dried mixture oflactose monohydrate (75%) with microcrystalline cellulose (25%) which iscommercially availble as Microcelac™. The amount of diluent or filler inthe tablets may conveniently range from about 20% to about 40% (w/w) andpreferably ranges from about 25% to about 32% (w/w).

The tablet may include a variety of one or more other conventionalexcipients such as binders, buffering agents, lubricants, glidants,thickening agents, sweetening agents, flavors, and colors. Someexcipients can serve multiple purposes.

Lubricants and glidants can be employed in the manufacture of certaindosage forms, and will usually be employed when producing tablets.Examples of lubricants and glidants are hydrogenated vegetable oils, e.ghydrogenated Cottonseed oil, magnesium stearate, stearic acid, sodiumlauryl sulfate, magnesium lauryl sulfate, colloidal silica, talc,mixtures thereof, and others known in the art. Interesting lubricantsand glidants are magnesium stearate, and mixtures of magnesium stearatewith colloidal silica. A preferred lubricant is hydrogenated vegetableoil type I, most preferably hydrogenated, deodorized Cottonseed oil(commercially available from Karlshamns as Akofine NF™ (formerly calledSterotex™)). Lubricants and glidants generally comprise 0.2 to 7.0% ofthe total tablet weight.

Other excipients such as coloring agents and pigments may also be addedto the tablets of the present invention. Coloring agents and pigmentsinclude titanium dioxide and dyes suitable for food. A coloring agent isan optional ingredient in the tablet of the present invention, but whenused the coloring agent can be present in an amount up to 3.5% based onthe total tablet weight.

Flavors are optional in the composition and may be chosen from syntheticflavor oils and flavoring aromatics or natural oils, extracts fromplants leaves, flowers, fruits and so forth and combinations thereof.These may include cinnamon oil, oil of wintergreen, peppermint oils, bayoil, anise oil, eucalyptus, thyme oil. Also useful as flavors arevanilla, citrus oil, including lemon, orange, grape, lime andgrapefruit, and fruit essences, including apple, banana, pear, peach,strawberry, raspberry, cherry, plum, pineapple, apricot and so forth,The amount of flavor may depend on a number of factors including theorganoleptic effect desired. Generally the flavor will be present in anamount from about 0% to about 3% (w/w).

As known in the art, tablet blends may be dry-granulated orwet-granulated before tabletting. The tabletting process itself isotherwise standard and readily practised by forming a tablet fromdesired blend or mixture of ingredients into the appropriate shape usinga conventional tablet press.

Tablets of the present invention may further be film-coated to improvetaste, to provide ease of swallowing and an elegant appearance. Manysuitable polymeric film-coating materials are known in the art. Apreferred film-coating material is hydroxypropyl methylcellulose HPMC,especially HPMC 2910 5 mPs·s. Other suitable film-forming polymers alsomay be used herein, including, hydroxypropylcellulose, andacrylate-methacrylate copolymers. Besides a film-forming polymer, thefilm coat may further comprise a plasticizer (e.g. propylene glycol) andoptionally a pigment (e.g. titanium dioxide). The film-coatingsuspension also may contain talc as an anti-adhesive. In immediaterelease tablets according to the invention, the film coat is small andin terms of weight accounts for less than about 3% (w/w) of the totaltablet weight.

Preferred dosage forms are those wherein the weight of the particles isat least 40% of the total weight of the total dosage form, that of thediluent ranges from 20 to 40%, and that of the disintegrant ranges from3 to 10%, the remainder being accounted for by one or more of theexcipients described hereinabove. As an example of a preferred oraldosage form comprising 200 mg of itraconazole, the following formula maybe given:

21.65% itraconazole (200 mg) 32.48% HPMC 2910 5 mPa · s (300 mg) 30.57%spray-dried lactose monohydrate:microcrystalline cellulose (75:25)mixture (282.4 mg) 8.49% crospolyvidone (78.4 mg) 2.79% talc (25.8 mg)0.93% hydrogenated vegetable oil Type I (8.6 mg) 0.28% colloidalanhydrous silica (2.6 mg) 0.24% magnesium stearate (2.2 mg), yielding97.43% tablet core, and 1.47% HPMC 2910 5 mPa · s (13.57) 0.37%propyleneglycol (3.39 mg) 0.29% talc (2.71 mg) 0.44% titanium dioxide(4.07 mg), yielding 2.57% film-coat.

Preferred dosage forms according to the present invention are those fromwhich at least 85% of the available itraconazole dissolves within 60minutes when a dosage form equivalent to 200 mg itraconazole is testedas set forth in USP test <711> in a USP-2 dissolution apparatus underconditions at least as stringent as the following: 900 ml phosphatebuffer, pH 6.0, 37° C. with paddles turning at 100 rpm. Tabletscomplying with the preceding definition can be said to have Q>85% (60′).Preferably, tablets according to the present invention will dissolvefaster and have Q>85% (15′), more preferably Q>85% (5′).

The present invention further concerns a process of preparing particlesas described hereinbefore, characterized by blending the components,extruding said blend at a temperature in the range of 120–300° C.,grinding the extrudate, and optionally sieving the particles.

The invention also concerns solid dispersions obtainable bymelt-extrusion of

-   (a) itraconazole or one of its stereoisomers or a mixture of two or    three or four of its stereoisomers, and-   (b) one or more pharmaceutically acceptable water-soluble polymers.

It is another object of the invention to provide a process of preparinga pharmaceutical dosage form as described hereinbefore, characterized byblending a therapeutically effective amount of particles as describedhereinbefore, with pharmaceutically acceptable excipients andcompressing said blend into tablets.

Further, this invention concerns particles as described hereinbefore,for use in preparing a pharmaceutical dosage form for oraladministration to a mammal suffering from a fungal infection, wherein asingle such dosage form can be administered once daily to said mammal.

The invention also relates to particles as described hereinbefore, foruse in preparing a pharmaceutical dosage form for oral administration toa mammal suffering from a fungal infection, wherein said dosage form canbe administered at any time of the day independently of the food takenin by said mammal.

The present invention also concerns the use of particles according to asdescribed hereinbefore, for the preparation of a pharmaceutical dosageform for oral administration to a mammal suffering from a fungalinfection, wherein a single such dosage form can be administered oncedaily to said mammal.

The present invention also concerns the use of particles as describedhereinbefore, for the preparation of a pharmaceutical dosage form fororal administration to a mammal suffering from a fungal infection,wherein said dosage form can be administered at any time of the dayindependently of the food taken in by said mammal.

The invention also relates to a method of treating a fungal infection ina mammal which comprises administering to said mammal an effectiveantifungal amount of itraconazole in a single oral dosage form which canbe administered once daily.

The invention also relates to a method of treating a fungal infection ina mammal which comprises administering to said mammal an effectiveantifungal amount of itraconazole in a single oral dosage form which canbe administered at any time of the day independently of the food takenin by said mammal.

The invention also relates to a pharmaceutical package suitable forcommercial sale comprising a container, an oral dosage form ofitraconazole as described hereinbefore, and associated with said packagewritten matter non-limited as to whether the dosage form can be takenwith or without food.

It has been observed that the tablets of the present invention showed aremarkably lower food-effect than the prior art Sporanox™ capsules. Thismeans that the difference between taking the medication after a meal orin fasted state is significantly less when the tablet of the presentinvention is administered than when Sporanox™ capsules are administered.This is of course a huge advantage because the medication can be takenin at any time during the day and is no longer dependent upon the intakeof a meal. Moreover, patients, who are feeling nauseous or who are notable to eat can still take the tablets of the present invention.

EXAMPLE 1

a) Preparation of Triaset®

A 40/60 (w/w) mixture of itraconazole (21.74 kg) and hydroxypropylmethylcellulose 2910 5 mPs·s⁽¹⁾ or HPMC 2910 5 mPs·s (32.11 kg) wereboth sieved and mixed in a planetary mixer until the mixture washomogenous. This physical mixture of itraconazole and HPMC is also knownas Triaset®.

b) Preparing the Melt Extrudate

1500 g of Triaset® was fed into a twin screw melt extruder of the typeAPV-Baker MP19 L/D 15having the following operating parameters:temperature of the first compartment was 245° C., temperature of thesecond compartment was 265° C., the twin screw had a rate of 20–300revolutions/min and was extruded during 120 minutes. The extrudate wasbrought in a hammer mill of type Fitzmill, the mesh of the sieve was0.125 inch (=0.32 cm) and revolving speed was 1640 revolutions perminute. The milled extrudate was again brought in a hammer mill, thistime with a sieve of mesh 0.063 inch (=0.16 cm) and a revolving speed of1640 revolutions per minute. Yield was 1169 g (78%).

c) Preparation of a Tabletting Mixture

Microcrystalline cellulose (351 g, 21% (w/w)), Crospovidone (117 g, 7%(w/w)), Aerosil (colloidal silicon dioxide) (5 g, 0.3% (w/w)) andSterotex (8 g, 0.5% (w/w)) were sieved and mixed together with themilled extrudate (1169 g, 71% (w/w)) using a planetary mixer until ahomogenous mixture was obtained (15 minutes).

d) Tabletting

Using the mixture obtained in c) 1450 oval biconvex half-scored tabletsof 706 mg (die length=17.6 mm, breadth=8.4 mm) were prepared on anExcenterpress Courtoy 27.

EXAMPLE 2

The process as described in example 1 was repeated, but the extrusionstep was carried out as follows:

1000 g of Triaset® was inserted into a meltextruder of the typeAPV-Baker MP19 L/D 15 having the following operating parameters:temperature of the first compartment was 170° C., temperature of thesecond compartment was 170° C., the twin screw had a rate of 450revolutions/min. The extrudate was brought in a hammer mill of typeFitzmill, the mesh of the sieve was 0.125 inch (=0.32 cm) and revolvingspeed was 1640 revolutions per minute. The milled extrudate was againbrought in a hammer mill, this time with a sieve of mesh 0.063 inch(=0.16 cm) and a revolving speed of 1640 revolutions per minute.

The tablets were prepared in the same manner as described in Example 1and had the following characteristics:

-   -   nominal weight: 706 mg    -   disintegation time: <15 minutes    -   hardness: >6 daN (deca Newton)    -   height: 6.7±0.1 mm

EXAMPLE 3

Itraconazole plasma levels in healthy volunteers after single oraladministration of 200 mg in two different formulations in fastingconditions.

Treatment with the available prior art itraconazole capsules

200 mg as two 100 mg coated cores-capsules (Sporanox®) in fastingconditions five volunteers

plasma level (ng/ml) time (h) mean value (S.D.) 0 ND⁽¹⁾ 1 26.8 (27.1) 2 125 (111) 3  128 (101) 4  110 (84.3) 5 84.5 (68.9) 6 71.1 (55.2) 8 54.5(44.3) 24  25.6 (20.3)

Treatment with tablets of the present invention as prepared in example1, i.e one 200 mg “melt extrusion tablet” in fasting conditions

plasma level (ng/ml) time (h) mean value (S.D.) 0 ND⁽¹⁾ 1 54.4 (51.3) 2 143 (97.8) 3  191 (111) 4  208 (124) 5  198 (136) 6  153 (107) 8  124(79) 24  44.5 (24.2)

This limited study in volunteers (n=5) shows that in fasted state themelt extrusion tablet gives a AUC of itraconazole (which is a measurefor the bioavailability of itraconazole) that is 2.3 times the AUC ofitraconazole when administered as 2 times a 100 mg capsule of Sporanox™.When using the non-parametric test (WILCOXON) this difference appears tobe significant at a confidence level of 90%.

EXAMPLE 4

a) Preparation of a Tabletting Mixture

A spray-dried mixture of lactose monohydrate (75%) and microcrystallinecellulose (25%) (2.824 kg, 30.57% (w/w)), Crospovidone (784 g, 8.49%(w/w)), Talc (258 g, 2.79% (w/w)), Aerosil (26 g, 0.28% (w/w)),magnesium stearate (22 g, 0.24% (w/w)) and Sterotex (86 g, 0.093% (w/w))were sieved and mixed together with the milled extrudate (5 kg, 54.13%(w/w)) using a planetary mixer until a homogenous mixture was obtained(15 minutes). All % (w/w) are based on the total weight of a film-coatedtablet.

b) Tabletting

Using the mixture obtained in a) 3,000 oval biconvex tablets of 900 mgwere prepared on an Excenterpress Courtoy 27.

c) Film-Coating

The tablets obtained in b) were film-coated using a suspensioncomprising by weight: HPMC 2910 5 mPs·s (8.5%), propylene glycol (2.1%),talc (1.7%), and titanium dioxide (2.6%) in demineralised water (85%).HPMC 2910 5 mPs·s was added to the purified water and mixed untilcompletely dispersed. The solution was left to stand until clear.Propylene glycol was added and mixed until uniform. Talc and titaniumdioxide were added to the solution and mixed until uniform. The tabletsobtained in d) were placed in a coating pan and the pigmented coatingsolution was sprayed onto the cores. Average tablet weight was 924.7 mg.

d) Packing

The coated tablets were packed into polyvinyl/aluminium foil blisterpacks, which in turn were packed into cardboard cartons.

e) Dissolution Properties

In-vitro dissolutions studies were performed on the 200 mg tabletformulation. The medium was 900 ml of 0.1 N HCl at 37° C. in Apparatus 2(USP 23, <711> Dissolution, pp. 1791–1793) (paddle, 100 rpm). Theconcentration of the active ingredient itraconazole dissolved in thetest medium was determined by removing a 3 ml sample at the indicatedtime, measuring its absorbance at 254 nm and calculating theconcentration therefrom.

The following results were obtained:

Calculated concentration (% w/w) of the active dose Time sample samplesample sample sample sample (min) 1 2 3 4 5 6 average 0 0.00 0.00 0.000.00 0.00 0.00 0.00 5 83.70 85.10 79.56 87.39 86.04 89.73 85.25 15 97.6597.79 97.34 97.20 97.29 100.62 97.98 30 97.43 98.78 98.82 100.71 98.8299.59 99.02 45 98.42 98.55 98.69 100.49 98.87 99.18 99.03 60 99.27 99.5499.36 100.44 98.91 99.23 99.46

EXAMPLE 5

a) Preparation of Particles <125 μm

1500 g of Triaset® was melt extruded as as described in example 1 andmilled in Fitzmill hammer mill at 4736 rpm and a sieve of 0.51 mm. Theparticle fraction with a size <125 μm was isolated by further sievingthrough a sieve No 120 (ASTM E 11-70); yield <10%.

b) Tabletting

A tabletting mixture having a composition as described in Example 4, butcomprising particles having a size <125 μm was prepared and compressedon a Korsch tabletting machine operating at a speed of 10,800tablets/hour, a compression pressure of 1500 to 1950 k/cm² (147–191.1MPa). The length of the die was 19 mm, breadth 9.5 mm, and the radius ofcurvature 9.57 mm. The tablets had the following characteristics:

-   -   nominal weight: 906.9 mg    -   maximum height: 5.88 mm    -   hardness: 11 daN    -   disintegration time: 2′15″    -   friability: 0%

1. A pharmaceutical dosage form comprising a therapeutically effective amount of particles consisting of a solid dispersion comprising (a) itraconazole, or one of its stereoisomers, or a mixture of two or three or four of its stereoisomers, and (b) one or more pharmaceutically acceptable water-soluble polymers, wherein the particle has a size of less than 600 μm, and wherein the dosage form comprises by weight based on the total weight of the dosage form: 21.65% itraconazole 32.48% HPMC 2910 5 mPs·s 30.57% spray-dried mixture of lactose monohydrate and microcrystalline cellulose in a 75:25 ratio 8.49% crospovidone 2.79% talc 0.93% hydrogenated vegetable oil Type I 0.28% colloidal anhydrous silica 0.24% magnesium stearate, yielding 97.43% tablet core, and 1.47% HPMC 2910 5 mPs·s 0.37% propyleneglycol 0.29% talc 0.44% titanium dioxide, yielding 2.57% film-coat.
 2. A dosage form according to claim 1 wherein the itraconazole is in a non-crystalline phase.
 3. A dosage form according to claim 1 wherein the solid dispersion is in the form of a solid solution comprising (a) and (b), or in the form of a dispersion wherein amorphous or microcrystalline (a) or amorphous or microcrystalline (b) is dispersed in a solid solution comprising (a) and (b).
 4. A dosage form according to claim 1 wherein the particle is obtained by melt-extrusion of the components and grinding, and optionally sieving.
 5. A dosage form according to claim 1 further comprising one or more pharmaceutically acceptable excipients.
 6. A dosage form according to claim 1 adapted for oral administration shaped as a tablet.
 7. A dosage form according to claim 6 surrounded by a film-coat comprising a film-forming polymer, a plasticizer and optionally a pigment.
 8. A dosage form according to claim 1 from which at least 85% of the available itraconazole dissolves within 60 minutes when a dosage form equivalent to 200 mg itraconazole is tested as set forth in USP test <711>in a USP-2 dissolution apparatus under conditions at least as stringent as the following: 900 ml phosphate buffer, pH 6.0, 37° C. with paddles turning at 100 rpm.
 9. A dosage form according to claim 1 wherein the particles are prepared by blending the components (a) and (b), extruding said blend at a temperature in the range of 120–300° C., grinding the extrudate, and optionally sieving the particles.
 10. A dosage form according to claim 1 prepared by blending a therapeutically effective amount of the particles with pharmaceutically acceptable excipients and compressing said blend into tablets.
 11. A pharmaceutical package suitable for commercial sale comprising a container, a pharmaceutical dosage form of itraconazole as claimed in claim 1, and associated with said package written matter non-limited as to whether the dosage form can be taken with or without food.
 12. A method of treating a fungal infection in a mammal comprising orally administering to the mammal an effective antifungal amount of itraconazole in a pharmaceutical dosage form as claimed in claim 1, wherein said pharmaceutical dosage from can be administered once daily.
 13. The method of claim 12, wherein said pharmaceutical dosage form can be administered at any time of the day independently of the food taken in by said mammal. 